Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain capillaries form a selective interface, the blood-brain barrier (BBB), between the neural parenchyma and the blood. The factors which regulate this interface are poorly understood. Both the iris and retina possess vascular beds that express some BBB characteristics; therefore, they provide attractive models to further our understanding of how blood-tissue interfaces are regulated. We have determined whether three BBB markers: the transferrin receptor, P-glycoprotein, and gamma-glutamyl transpeptidase (gamma-GTP), can be localized in the capillaries of the rat retina and iris. We have also compared, in retina and iris, the relationship which GFAP-positive cells have with the blood vessels to the expression of the three BBB markers by the vessels. Immunocytochemistry revealed that capillaries throughout the retina express P-glycoprotein and the transferrin receptor. Retinal vessels do not show detectable gamma-GTP activity. GFAP-positive cells ensheath capillaries in the nerve fibre layer of the retina. Of the three BBB characteristics we examined, iridial vessels expressed only one of them: P-glycoprotein. In the iris, GFAP-positive cells do not ensheath capillaries. From our results we conclude that all BBB characteristics do not have to be expressed and regulated in capillaries as a unit. Our results, in combination with those of earlier studies, suggest that the expression of some BBB features does not require intimate contact between capillaries and astrocytes or astrocyte-like cells. Barrier maintenance appears to be a complex process which involves the integration of several factors.
Brain Res 1993 Dec 03
PMID:The relationship of astrocyte-like cells to the vessels that contribute to the blood-ocular barriers. 790

A P-glycoprotein homologue has been previously identified in Plasmodium falciparum and was termed PGH 1. This paper describes studies analyzing the phosphorylation of the PGH 1 molecule. It was found, by metabolic labeling with [32P]orthophosphate, that PGH 1 was phosphorylated throughout the entire asexual erythrocytic life cycle of the parasite, with the maximum level of 32P incorporation during the trophozoite and schizont stages. Incubation of trophozoites with modulators of mammalian protein kinases suggests that a Ca(2+)-dependent protein kinase is involved in phosphorylation of PGH 1. PGH 1 could also be phosphorylated in the presence of gamma-32P ATP on purified digestive vacuoles where this protein has previously been localized. Two-dimensional phospho-amino acid analysis revealed that PGH 1 was phosphorylated on serine and threonine residues and the pattern of amino acid phosphorylation was similar for PGH 1 phosphorylated in infected red blood cells and on purified digestive vacuoles. PGH 1 phosphorylation in the presence of some antimalarial drugs was analyzed and it was found that neither chloroquine nor compounds that modulate chloroquine resistance had any effect on PGH 1 phosphorylation.
Mol Biochem Parasitol 1993 Dec
PMID:Phosphorylation of a P-glycoprotein homologue in Plasmodium falciparum. 790 21

The virus-associated T cell leukaemias/lymphomas are characterized by a poor prognosis primarily because of the rapid emergence of drug resistance which may lead to failure of subsequent chemotherapy. We report here a case of Epstein-Barr virus-associated T cell lymphoma which relapsed soon after chemotherapy and radiotherapy. The neoplastic cells of the relapsed tumour expressed high levels of multi-drug resistance gene (mdr1)-related P-glycoprotein and glutathione-S-transferase-pi, both of which were absent in the pre-chemotherapy tumour tissues. Empirical treatment with oral 13-cis-retinoic acid (RA) was then given with subsequent complete disappearance of the tumour. The therapeutic effect of RA appears to act through an apoptotic process. In accordance with our previous report of a successful salvage of a refractory Ki-1 large cell lymphoma. RA appears to be a potentially useful drug for some specific type T-cell lymphomas.
Br J Haematol 1993 Dec
PMID:Retinoic acid-induced apoptosis and regression of a refractory Epstein-Barr virus-containing T cell lymphoma expressing multidrug-resistance phenotypes. 791 55

The levels of several potential indicators of drug resistance were measured in tumor and corresponding normal tissue of 55 untreated patients with lung cancer. The resistance parameters include glutathione (GSH) level, activities of the enzymes glutathione transferase (GST), glutathione peroxidase (GPx) and O6-alkylguanine-DNA alkyltransferase (ATase), as well as expression of P-glycoprotein (Pgp). Median values of GSH, GST and GPx were significantly higher in tumor than in normal tissue of non-small-cell lung cancer (NSCLC) or of small-cell lung cancer (SCLC), whereas ATase was elevated in tumor tissue of NSCLC only. Pgp expression as determined by Western blotting was significantly lower in tumor than in normal tissue of NSCLC. Resistance-parameter expression did not correlate with stage of disease or age of the patients. We found a negative correlation between smoking intensity and GSH level in normal tissue. Our findings indicate that the fundamental differences in chemosensitivity between SCLC and NSCLC cannot be explained by differences in the GSH-system or in the expression of Pgp. However, the level of ATase activity may be one of the factors responsible for the difference in chemosensitivity.
Int J Cancer 1994 Dec 01
PMID:Parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer. 796 Feb 35

Metastatic malignant melanoma is considered a chemotherapy-refractory malignancy. A few previous studies have delivered contradictory results regarding the presence and functionality of P-glycoprotein (P-gp), a transmembranous protein associated with the classical multidrug resistance (cMDR), in malignant melanoma. Therefore we have investigated this issue on 33 cell lines established from primary and metastatic lesions of human malignant melanoma, comparing different cMDR detection methods. Immunocytochemically 33% of the cell lines stained positive for P-gp. The data correlated with those of a P-gp-radioimmunometric (antibody-binding) assay. When RT-PCR was used for MDR-1 mRNA determination, 76% of the melanoma cell lines scored positive. Slot-blot analysis was seen to be less sensitive than RT-PCR. Results from the functional P-gp assays, using daunomycin (DM) as MDR-substrate, showed no influence of P-gp expression on drug accumulation and cytotoxicity. However, the cMDR-modifier verapamil (VP) significantly increased both parameters in those melanoma cells with the highest P-gp levels. We conclude that cMDR is apparently not the decisive but probably a complementary protective mechanism against toxic agents in malignant melanoma.
Int J Cancer 1994 Dec 01
PMID:Intrinsic MDR-1 gene and P-glycoprotein expression in human melanoma cell lines. 796 Feb 46

The tissue distribution of P-glycoprotein (Pgp) and the structurally related cystic fibrosis transmembrane conductance regulator (CFTR) is apparently mutually exclusive, particularly in epithelial; where one protein is expressed the other is not. To study the possible function(s) of Pgp and its potential effects on CFTR expression in epithelia, HT-29 colon adenocarcinoma cells, which constitutively express CFTR, were pharmacologically adapted to express the classical multidrug resistance (MDR) phenotype (Pgp+). Concomitant with the appearance of Pgp and MDR phenotype (drug resistance, reduced drug accumulation and increased drug efflux), CFTR levels and cAMP-stimulated Cl conductances were markedly decreased compared to wild-type HT-29 (Pgp-) cells (as shown using the whole cell patch clamp technique). Removal of drug pressure led to the gradual decrease in Pgp levels and MDR phenotype, as evidenced by increased rhodamine 123 accumulation (Pgp-Rev). Concomitantly, CFTR levels and cAMP-stimulated Cl- conductances increased. The cell responses of Pgp/Rev cells were heterogeneous with respect to both Pgp and CFTR functions. We also studied the possible contribution to Pgp to hypotonically activated (HCS) ion conductances. K+ and Cl- effluxes from Pgp- cells were markedly increased by HCS. This increase was twice as high as that induced by the cation ionophore gramicidin; it was blocked by the Cl- channel blocker DIDS (4,4'-disothiocyano-2,2'-disulfonic stilbene) and required extracellular Ca2+. In Pgp+ cells, the HCS-induced fluxes were not significantly different from those of Pgp- cells. Verapamil (10 microM), which caused 80% reversal of Pgp-associated drug extrusion, failed to inhibit the HCS-evoked Cl- efflux of Pgp+ cells. Similarly, HCS increased Cl- conductance to the same extent in Pgp-, Pgp+ and Pgp-Rev cells. Verapamil (100 microM), but not 1,9-dideoxyforskolin (50 and 100 microM), partially inhibited the HCS-evoked whole cell current (WCC) in all three lines. Since the inhibition by verapamil was not detected in the presence of the K+ channel blocker Ba2+ (3 mM), it is suggested that verapamil affects K+ and not Cl- conductance. We conclude that hypotonically activated Cl- and K+ conductances are similar in HT-29 cells irrespective of Pgp expression. Expression of high levels of Pgp in HT-29 cells confers no physiologically significant capacity for cell volume regulation.
J Cell Physiol 1994 Dec
PMID:Effects of P-glycoprotein expression on cyclic AMP and volume-activated ion fluxes and conductances in HT-29 colon adenocarcinoma cells. 796 23

A bladder carcinoma cell line (J82) was selected for resistance to the new vinca alkaloid navelbine. The resistance factor of the resistant subline (J82-NVB) to navelbine was 17. P-glycoprotein was not detected in the membrane of J82-NVB cells. The lack of cross-resistance to multidrug-resistant (MDR) drugs such as doxorubicin, epipodophyllotoxins and colchicine, the absence of increase in navelbine efflux and the fact that a reduced accumulation of the drug cannot account for the resistance level confirmed that the phenotype of resistance of J82-NVB cells is not a classical MDR phenotype. Moreover, verapamil did not reverse the resistance of J82-NVB cells. The cells were cross-resistant to vinca alkaloids and taxoids which share the same target protein: tubulin. Analysis of microtubules using immunofluorescence showed that disassembly of the microtubular network occurred for the same concentration of navelbine in sensitive and resistant cells. However, after treatment with a concentration of navelbine inducing depolymerisation in both sensitive and resistant cells, reassembly of the microtubular network was observed only in resistant cells. This study suggests that the mechanism of resistance of J82-NVB cells involves recovery from the inhibition of microtubule dynamics induced by drug treatment.
Br J Cancer 1994 Dec
PMID:Characterisation of a navelbine-resistant bladder carcinoma cell line cross-resistant to taxoids. 798 Oct 63

Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transfer pi (GST-pi) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-pi was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21%), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-170-negative tumours (P < 0.05). However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-pi was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-pi was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.
Br J Cancer 1994 Dec
PMID:P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia. 798 Oct 66

Active [3H]vinblastine (VBL) transport (efflux) was documented for inside-out plasma membrane vesicles from murine erythroleukemia cells (MEL/VCR-6) resistant to vinca alkaloids and overexpressing MDR 3 P-glycoprotein (P-gp) 80-fold. Uptake of [3H]VBL at 37 degrees C by these inside-out vesicles, but not rightside-out vesicles or inside-out vesicles from wild-type cells, was obtained in the form of a rapid, initial phase (0-1 min) and a slower, later phase (> 1 min). The rapidity of each phase correlated with relative P-gp content among different MEL/VCR cell lines. The initial MDR-specific phase was temperature- and pH-dependent (optimum at pH 7), osmotically insensitive, and did not require ATP. The second MDR-specific phase was temperature-dependent, osmotically sensitive, and strictly dependent upon the presence of ATP (Km = 0.37 +/- 0.04 mM). Although other triphosphate nucleotides were partially effective in replacing ATP, the nonhydrolyzable analogue ATP gamma S (adenosine 5'-O-(thiotriphosphate)) was ineffective. This time course appears to represent tandem binding of [3H]VBL by P-gp and its mediated transport, with the latter process representing the rate-limiting step. In support of this conclusion, both binding and transport were inhibited by verapamil, quinidine, and reserpine, all known to be inhibitors of photoaffinity labeling of P-gp, but only transport was inhibited by C219 anti-P-gp antibody or orthovanadate. Although the rate of transport of [3H]VBL was 7-7.5-fold lower than the rate of binding (Vmax = 104 +/- 15 pmol/min/mg protein, Kon = 1.5 - 2 x 10(5) mol-1 s-1) to P-gp, each phase exhibited saturation kinetics and values for apparent Km and KD for each process were approximately the same (215 +/- 35 and 195 +/- 30 nM). Intravesicular accumulation of [3H]VBL was almost completely eliminated by high concentrations of nonradioactive VBL, suggesting that simple diffusion does not contribute appreciably to total accumulation of [3H]VBL in this vesicle system. This could be at least partially explained by the fact that these inside-out vesicles under the conditions employed did not maintain a P-gp mediated pH gradient. However, ATP-dependent, intravesicular accumulation of osmotically sensitive [3H]VBL occurred against a substantial permeant concentration gradient in both a time- and concentration-dependent manner consistent with an active, saturable process.
J Biol Chem 1994 Dec 09
PMID:Functional studies of P-glycoprotein in inside-out plasma membrane vesicles derived from murine erythroleukemia cells overexpressing MDR 3. Properties and kinetics of the interaction of vinblastine with P-glycoprotein and evidence for its active mediated transport. 798 45

The surface and intracellular expression of mdrI-P-glycoprotein in parental drug-sensitive human breast cancer cells (MCF-7) and their multidrug-resistant (MDR) variants has been studied by using the monoclonal antibodies (MAbs) MM4.17 and MRK-16, which recognize 2 different epitopes of the drug efflux pump molecule. Fluorescence microscopic observations showed that P-glycoprotein, in addition to being located at the cell surface, can also be found in the Golgi apparatus of resistant cells. To confirm this finding, Golgi apparatus and P-glycoprotein were double-labelled with wheat-germ agglutinin (WGA) and MAb MM4.17. Laser scanning confocal microscopy indicated that, in MDR cells, Adriamycin mainly accumulated cytoplasmically in a perinuclear region. This accumulation proved to be modulated by pre-treatment with verapamil or ATP depletion. Moreover, the vital staining of Adriamycin-treated MDR cells, performed with the fluorescent lipid N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]- 6-aminocaproyl sphingosine (C6-NBD-ceramide), revealed that the anthracyclinic antibiotic was located in the Golgi apparatus. All these results indicate that the drug transporter is located in the Golgi apparatus, in which Adriamycin molecules also accumulate.
Int J Cancer 1994 Dec 15
PMID:P-glycoprotein expression in the Golgi apparatus of multidrug-resistant cells. 798 20


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